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Design, Synthesis and In Vitro Evaluation of 4-Androstene-3,17-dione/Adenosine Hybrid Compounds as Bisubstrate Inhibitors of Type 3 17β-Hydroxysteroid Dehydrogenase

[ Vol. 2 , Issue. 4 ]

Author(s):

Marie Berube, Yannick Laplante and Donald Poirier   Pages 329 - 347 ( 19 )

Abstract:


Steroidogenic enzyme type 3 17β-hydroxysteroid dehydrogenase (17β-HSD) is an important therapeutic target for androgen-sensitive diseases. This enzyme selectively reduces the C17 ketone of 4-androstene-3,17-dione (Δ4-dione), thus producing testosterone (T) using NADPH as cofactor. Our group previously synthesized hybrid (estradiol/adenosine) inhibitors that successfully inhibit the biosynthesis of the potent estrogen estradiol by type 1 17β-HSD. To similarly lower the level of the potent androgen testosterone, inhibitors of type 3 17β-HSD were designed and synthesized applying the same hybrid (substrate/cofactor) strategy. Two chemical approaches were developed to join the three components of the bisubstrate inhibitor (the substrate Δ4-dione, an alkyl spacer and the cofactor moiety adenosine). An alkylation in the α position of steroidal 17-ketone or a cross-metathesis was used as a key step to efficiently join the substrate and the alkyl spacer, whereas an esterification was employed to link the spacer to adenosine. An enzymatic assay in homogenated HEK-293 cells overexpressing type 3 17β-HSD revealed that the best inhibitors of that series are those bearing an alkyl side-chain spacer of 11 or 12 methylenes: inhibition of 69 and 78% at 1 μM were respectively observed. As expected, these bisubstrate inhibitors were less potent in intact cells than in homogenated cells. However, both enzymatic assays revealed that the strategy of substrate/cofactor dual inhibitors seems to work for type 3 17β-HSD, although the inhibitors designed have not been optimized yet.

Keywords:

crossmetathesis, androgen, hormone, steroid, type 3 17β-HSD, 17β-hydroxysteroid dehydrogenase, enzyme, Inhibitor

Affiliation:

Medicinal Chemistry Division, Oncology and Molecular Endocrinology Research Center, CHUQ Pavillon CHUL, 2705, Laurier Boulevard, Quebec, G1V 4G2, Canada.



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